Implication of bone marrow adipose tissue in bone homeostasis during osteoarthritis

Objective: To explore the role of bone marrow adipocytes (BMAds) in osteoarthritis (OA). Methods: Male and female C57BL/6 mice (n=4/group) underwent meniscectomy (MNX) or SHAM surgery. OA was determined using OARSI score and the number of perilipin+ adipocytes was quantified. Mesenchymal Stromal Cells (MSCs) from MNX and SHAM mice were differentiated into osteoblasts and adipocytes. Human adipocytes and MSCs (n=8) were enzymatically isolated from epiphyseal and metaphyseal marrow, and from subcutaneous adipose tissue (SCAT) of hip OA patients. Human OA MSCs were differentiated into osteoblasts and adipocytes (OA-Diff-hAdipo). Gene expression patterns of epiphyseal and metaphyseal BMAds, SCAT adipocytes and OA-Diff-hAdipo were evaluated by RNAseq (n=4). The effect conditioned media from OA epiphyseal bone (n=5) on the alkaline phosphatase (ALP) activity and mineralization kinetics was assessed in vitro. Results: Increase in BMAd density was positively correlated with cartilage degradation in MNX mice. OA modified the differentiation capacity of MSCs, accelerating adipocyte differentiation and failing to produce osteoblasts in both human and mice. Human epiphyseal, metaphyseal and SCAT adipocytes from the same OA patients each displayed a specific transcriptome, suggesting different functions. Enrichment analysis defined metaphyseal OA-BMAds as cells implicated in hematopoietic stem cell differentiation. On the other hand, epiphyseal OA-BMAds were considered as osteogenic cells showing an up-regulation of genes related to bone mineralization and remodeling. Specifically, OA epiphysis-secreted molecules decreased ALP activity and altered in vitro the mineralization process. Conclusion: All these results support the emergence of BMAds as new cell partners in OA, opening new venues for therapeutic approaches.